The synthesis and characterization of novel prodrugs of the antiviral nucleosides acyclovir, penciclovir, and lamivudine are proposed with the purpose of identifying an agent with improved efficacy in the treatment of hepatitis B. The proposed prodrugs are designed to target the nucleosides selectively to the liver in their monophosphate form, and to enhance significantly the formation of the corresponding nucleoside triphosphates (NTP's), which are potent inhibitors of hepatitis B virus (HBV) polymerase. Enhanced hepatic NTP formation is likely to confer more rapid and complete suppression of HBV replication, and consequently to prevent the emergence of drug resistance, a major problem with current therapies. Studies are planned that will address (a) prodrug activation by a liver-specific enzyme (b) prodrug activation and phosphorylation in isolated hepatocytes and (c) prodrug pharmacokinetics and hepatic NTP generation in the rat. A key indicator for the success of the prodrug approach and its therapeutic potential is the temporal profile of hepatic NTP levels in vivo relative to parent nucleoside. A favorable profile will provide the impetus for additional studies envisaged for phase II of the proposal: the assessment of efficacy in animal models of HBV and the toxicological evaluations necessary to support clinical development. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE